Molecular structure of the dihydropyridazinone cardiotonic 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one, a potent inhibitor of cyclic AMP phosphodiesterase

Abstract

The cardiotonic 1,3-dihydro-3,3-dimethyl-5(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one (1, LY195115) is a potent, competitive inhibitor (Ki = 80 nM) of sarcoplasmic reticulum derived phosphodieterase (SR-PDE). Moreover, the compound is a potent positive inotrope both in vitro and in vivo. To assist further cardiotonic drug-design studies, we have mapped the three-dimensional structure of 1 using X-ray crystallography. From a global veiwpoint, this drug was essentially planar, but two small regions of nonplanarity were apparent. These involved the geminal methyl substituents in the indol-2-one moiety and the C5'' methylene unit of the dihydropyridazinone ring. Because of our previous studies involving the bipyridine cardiotonics amrinone and milrinone, the conformational relationship between the plane of the phenyl ring and the horizontal symmetry plane defined by N2'', C3'', and C4'' of 1 was of particular interest. The C6-C5-C3''-C4'' dihedral angle was -2.7.degree., whereas the C6-C5-C3''-N2'' dihedral angle was 174.6.degree.. Therefore the two rings maintain a high degree of coplanarity. Compound 4, the congener of 1 possessing a completely unsaturated pyridazinone ring was also studied. In terms of inotropic activity, this compound, devoid of any puckering in the pyridazinone moiety, was equipotent with 1. Methyl substitution at the 4-position of the dihydropyridazinone and pyridazinone rings provided disparate results. Compound 2, the 4-methyl analogue of 1, was 2-fold more potent than 1, and the methyl substituent probably caused only minor perturbations in overall molecular topology. However 5, the 4-methyl analogue of the pyridazinone 4, was 4.4-fold less active than 4, perhaps as a result of methyl-induced molecular nonplanarity.